INTRODUCTION Multiple system atrophy (MSA) and Lewy body disorders, including dementia with Lewy bodies (DLB) and Parkinson's disease (PD), are synucleinopathies that may manifest with prominent autonomic failure. Over the past 5 years, we have shown that in MSA there is loss of specific neuronal groups in the medulla, which is more severe than in PD and could contribute to the autonomic and respiratory manifestations of MSA. Whether the same occurs in DLB is still undetermined. Involvement of hypothalamic autonomic neurons may contribute to the manifestations of MSA and other synucleinopathies, but this possibility has not yet been systematically explored. Our central hypothesis is that (1) there is involvement of specific medullary and hypothalamic neuronal groups controlling autonomic and respiratory functions in MSA;(2) this involvement is more severe than in Lewy body disorders;and (3) this difference is reflected by the different characteristics and degree of severity of autonomic and respiratory impairment in these synucleinopathies. To assess these hypotheses, we plan to perform quantitative analysis of neurochemically defined cell groups in the medulla and hypothalamus of neuropathologically confirmed cases of MSA, DLB, PD and age-matched controls. We also plan to perform autonomic studies and assess the ventilatory responses to hypoxia and hypercapnia in patients with clinical diagnoses of MSA, DLB, or PD and age-matched controls. Our specific aims are (1) to determine whether in DLB there is involvement of tyrosine hydroxylase (TH), tryptophan hydroxylase (TrOH), or neurokinin-1 (NK-1R) receptor immunoreactive neurons in VLM and medullary raphe and compare this involvement with that seen in MSA;(2) to correlate the medullary neuropathological findings with the results of autonomic function and ventilatory drive in patients with clinically diagnosed MSA, DLB, or PD;(3) to determine whether in MSA there is involvement of neurons immunoreactive for TH, arginine vasopressin (AVP), oxytocin (OXT) or corticotrophin releasing factor (CRF) in the posterior portion of the hypothalamic paraventricular nucleus (PVN), presumably involved in autonomic control;and (4) to determine whether in MSA there is sparing of magnocellular AVP neurons in the supraoptic nucleus (SON) and PVN. Our studies will provide further insight into the central neuropathological substrate for autonomic and respiratory manifestations of MSA and Lewy body disorders and provide potential targets for therapeutic intervention.